CN1914200A - Nicotinic acetylcholine receptor ligands - Google Patents

Nicotinic acetylcholine receptor ligands Download PDF

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CN1914200A
CN1914200A CNA2004800412792A CN200480041279A CN1914200A CN 1914200 A CN1914200 A CN 1914200A CN A2004800412792 A CNA2004800412792 A CN A2004800412792A CN 200480041279 A CN200480041279 A CN 200480041279A CN 1914200 A CN1914200 A CN 1914200A
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disease
azabicyclic
oct
compound
fragrance
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格伦·欧内斯特
罗伯特·雅各布斯
艾菲奥恩·菲利普斯
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AstraZeneca AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Compounds of formula (I), wherein D, Ar<1>, E and Ar<2> are as defined in the specification, processes for preparing them, pharmaceutical compositions containing them and their use in therapy, especially in the treatment or prophylaxis of psychotic and intellectual impairment disorders.

Description

Nicotinic acetylcholine receptor ligands
Technical field
The present invention relates to have new diaryl methane amide or its pharmaceutically useful salt of the outflow effect of low P-glycoprotein-mediation, prepare their method, contain their pharmaceutical composition and the purposes in treatment thereof.The present invention be more particularly directed to have P-glycoprotein-mediation effusive, as the compound of the part of alpha 7 nicotinic acetylcholine receptors (α 7nAChRs).
Background of invention
Compound in conjunction with nicotinic acetylcholine receptor is being used for the treatment of the disease widely that relates to cholinergic function decline, as Alzheimer's, cognition or attention illness, anxiety disorder, dysthymia disorders, smoking is given up, neuroprotective, schizophrenia, analgesia, purposes in Tourette's syndrome and the Parkinson's disease has been discussed at (1995) " Nicotinic AcetylcholineReceptors:Molecular Biology; Chemistry and Pharmacology " such as McDonald, Chapter 5 inAnnual Reports in Medicinal Chemistry, vol.30, pp.41-50, Academic Press Inc., San Diego, CA; " Neuronal Nicotinic AcetylcholineReceptors, " Drug News ﹠amp and in (1994) such as Williams; Perspectives, vol.7 is among the pp.205-223.
The ability that medicine enters central nervous system (CNS) influences this compound in fact and whether has the CNS activity.Medicine is excluded and is considered to by hemato encephalic barrier (BBB) mediation outside CNS, and hemato encephalic barrier is the close-connected endotheliocyte of one deck.The mechanism of action that it is believed that BBB is the outflow effect of passive membrane permeability and P-glycoprotein mediation, and it mediates medicine in fact and whether can enter CNS or get rid of outside CNS.Therefore, the high passive membrane permeability and the forfeiture of outflow effect might help the exposure (Kelly M.Mahar Doan etc., JPET 3031029-1037, (2002)) of CNS.
Invention is described
The present invention relates to have the nicotinic acetylcholine receptor-active formula I compound of the outflow effect of astonishing low P-glycoprotein-mediation:
Wherein:
D represents oxygen or sulphur;
E represents singly-bound, oxygen, sulphur, or NR 1
Ar 1Be selected from 5-or the 6-person's fragrance or the assorted aromatic nucleus of ortho position replacement with 0,1 or 2 nitrogen-atoms, 0 or 1 Sauerstoffatom and 0 or 1 sulphur atom, or be selected from and have 0,1,2 or 3 nitrogen-atoms, 8-, the 9-that the ortho position of 0 or 1 Sauerstoffatom and 0 or 1 sulphur atom replaces or 10-person's condensed fragrance or assorted aromatic nucleus system, described fragrance or assorted aromatic nucleus or member ring systems have and are selected from-C 1-C 6Alkyl ,-C 2-C 6Alkenyl ,-C 2-C 6Alkynyl, halogen ,-CN ,-NO 2,-CF 3,-S (O) nR 2,-NR 2R 3-CH 2NR 2R 3,-OR 2,-CH 2OR 2Or-CO 2R 4Ortho position-substituting group;
Ar 2Be selected from 5-or 6-person's fragrance or assorted aromatic nucleus with 0,1 or 2 nitrogen-atoms, 0 or 1 Sauerstoffatom and 0 or 1 sulphur atom;
Ar wherein 2Be not substituted or have 1,2 or 3 and be independently selected from-R 2,-C 1-C 6Alkyl ,-C 2-C 6Alkenyl ,-C 2-C 6Alkynyl, halogen ,-CN ,-NO 2,-CF 3,-S (O) nR 2,-NR 2R 3,-CH 2NR 2R 3,-OR 2,-CH 2OR 2Or-CO 2R 4Substituting group;
R 2And R 3The each appearance, be independently selected from hydrogen ,-C 1-C 4Alkyl, aryl, heteroaryl ,-C (O) R 4,-C (O) NHR 4,-CO 2R 4Or-SO 2R 4, or
R 2And R 3Be combined into-(CH 2) jG (CH 2) k-, wherein G is oxygen, sulphur, NR 4, or chemical bond;
J is 2,3 or 4;
K is 0,1 or 2;
N is 0,1 or 2, and
R 4The each appearance, be independently selected from hydrogen ,-C 1-C 4Alkyl, aryl, or heteroaryl.
The present invention also comprises steric isomer, enantiomer, the interior hydrolyzable precursor of body and the pharmaceutically useful salt of formula I compound, the pharmaceutical composition and the preparation that contain them, use separately they or with the compound of other therapeutic activity or the method for material combination therapy disease and illness, be used to prepare their method and intermediate, they are as the purposes of medicine, they in the preparation medicine purposes and for the purposes of diagnosis and analysis purposes.
The compounds of this invention with low P-glycoprotein-mediation outflow effect is following formula I compound:
Figure A20048004127900091
Wherein:
D represents oxygen or sulphur;
E represents singly-bound, oxygen, sulphur, or NR 1
Ar 1Be selected from 5-or the 6-person's fragrance or the assorted aromatic nucleus of ortho position replacement with 0,1 or 2 nitrogen-atoms, 0 or 1 Sauerstoffatom and 0 or 1 sulphur atom, or being selected from 8-, 9-or 10-person's condensed fragrance or the assorted aromatic nucleus system that ortho position with 0,1,2 or 3 nitrogen-atoms, 0 or 1 Sauerstoffatom and 0 or 1 sulphur atom replaces, described fragrance or assorted aromatic nucleus or member ring systems have and are selected from-C 1-C 6Alkyl ,-C 2-C 6Alkenyl ,-C 2-C 6Alkynyl, halogen ,-CN ,-NO 2,-CF 3,-S (O) nR 2,-NR 2R 3,-CH 2NR 2R 3,-OR 2,-CH 2OR 2Or-CO 2R 4Ortho position-substituting group; Ar 2From the 5-with 0,1 or 2 nitrogen-atoms, 0 or 1 Sauerstoffatom and 0 or 1 sulphur atom or 6-person's fragrance or assorted aromatic nucleus;
Ar wherein 2Be not substituted or have 1,2 or 3 and be independently selected from-R 2,-C 1-C 6Alkyl ,-C 2-C 6Alkenyl ,-C 2-C 6Alkynyl, halogen ,-CN ,-NO 2,-CF 3,-S (O) nR 2,-NR 2R 3,-CH 2NR 2R 3,-OR 2,-CH 2OR 2Or-CO 2R 4Substituting group;
R 2And R 3The each appearance, be independently selected from hydrogen ,-C 1-C 4Alkyl, aryl, heteroaryl ,-C (O) R 4,-C (O) NHR 4,-CO 2R 4Or-SO 2R 4, or
R 2And R 3Be combined into-(CH 2) jG (CH 2) k-, wherein G is oxygen, sulphur, NR 4, or chemical bond;
J is 2,3 or 4;
K is 0,1 or 2;
N is 0,1 or 2, and R 4The each appearance, be independently selected from hydrogen ,-C 1-C 4Alkyl, aryl, or heteroaryl, and
In its steric isomer, enantiomer, body hydrolyzable precursor with and pharmaceutically useful salt.
Concrete The compounds of this invention is the R-isomer according to the formula I compound of formula II,
Figure A20048004127900101
Wherein D, Ar 1, E and Ar 2Define in the compound suc as formula I.
Those compounds that other concrete The compounds of this invention are formula I, wherein:
D represents oxygen or sulphur;
E represents singly-bound, oxygen, sulphur, or NR 1
Ar 1Be selected from 5-or the 6-person's fragrance or the assorted aromatic nucleus of ortho position replacement with 0,1 or 2 nitrogen-atoms, 0 or 1 Sauerstoffatom and 0 or 1 sulphur atom, or being selected from 8-, 9-or 10-person's condensed fragrance or the assorted aromatic nucleus system that ortho position with 0,1,2 or 3 nitrogen-atoms, 0 or 1 Sauerstoffatom and 0 or 1 sulphur atom replaces, described fragrance or assorted aromatic nucleus or member ring systems have and are selected from-C 1-C 6Alkyl, halogen ,-CN ,-NO 2,-CF 3,-NR 2R 3,-OR 2, or-CO 2R 4Ortho position-substituting group;
Ar 2Be selected from 5-or 6-person's fragrance or assorted aromatic nucleus with 0,1 or 2 nitrogen-atoms, 0 or 1 Sauerstoffatom and 0 or 1 sulphur atom;
Ar wherein 2Be unsubstituted or have 1,2 or 3 and be independently selected from-R 2,-C 1-C 6Alkyl ,-C 2-C 6Alkenyl ,-C 2-C 6Alkynyl, halogen ,-CN ,-NO 2,-CF 3,-S (O) nR 2,-NR 2R 3,-CH 2NR 2R 3,-OR 2,-CH 2OR 2Or-CO 2R 4Substituting group;
R 2And R 3The each appearance, be independently selected from hydrogen ,-C 1-C 4Alkyl, aryl, heteroaryl ,-C (O) R 4,-C (O) NHR 4,-CO 2R 4Or-SO 2R 4, or
R 2And R 3Be combined into-(CH 2) jG (CH 2) k-, wherein G is oxygen, sulphur, NR 4, or chemical bond;
J is 2,3 or 4;
K is 0,1 or 2;
N is 0,1 or 2, and
R 4The each appearance, be independently selected from hydrogen ,-C 1-C 4Alkyl, aryl, or heteroaryl, and
In its steric isomer, enantiomer, body hydrolyzable precursor with and pharmaceutically useful salt.
The compounds of this invention is those formulas I compound more specifically, wherein:
D represents oxygen;
E represents singly-bound;
Ar 1Be selected from 5-or 6-person's fragrance or assorted aromatic nucleus that ortho position with 0,1 or 2 nitrogen-atoms, 0 or 1 Sauerstoffatom and 0 or 1 sulphur atom replaces, described fragrance or assorted aromatic nucleus or have is selected from-C 1-C 6Alkyl, halogen ,-CN ,-NO 2,-CF 3,-NR 2R 3,-OR 2Or-CO 2R 4Ortho position-substituting group;
Ar 2Be selected from 5-or 6-person's fragrance or assorted aromatic nucleus with 0,1 or 2 nitrogen-atoms, 0 or 1 Sauerstoffatom and 0 or 1 sulphur atom, and
In its steric isomer, enantiomer, body hydrolyzable precursor with and pharmaceutically useful salt.
The compounds of this invention is those formulas I compound more specifically, wherein:
D represents oxygen;
E represents singly-bound;
AR 1Be selected from 5-or 6-person's fragrance or assorted aromatic nucleus that ortho position with 0,1 or 2 nitrogen-atoms, 0 or 1 Sauerstoffatom and 0 or 1 sulphur atom replaces, described fragrance or assorted aromatic nucleus have be selected from-CN ,-NO 2,-CF 3, or-OR 2Ortho position-substituting group;
Ar 2Be selected from phenyl or pyridyl, and
In its steric isomer, enantiomer, body hydrolyzable precursor with and pharmaceutically useful salt.
Other concrete The compounds of this invention is those formulas I compound, and wherein D is O; Or its enantiomer, with and pharmaceutically useful salt.
The compounds of this invention is those formulas I compound, wherein Ar more specifically 1Be selected from phenyl or thienyl and Ar 2Be selected from and have optional as defined above substituent phenyl, pyridyl, furyl or thienyl.
Concrete compound of the present invention be those compounds described herein with and pharmacologically acceptable salt.
Another aspect of the present invention relates to the compound with formula I, and wherein one or more atoms are radio isotope of identical element.At the preferred version of the present invention aspect this is that formula I compound is carried out tritiated.By add radiolabeled starting raw material or, with regard to tritiated, change hydrogen into tritium with known method, synthesize these radio-labeled compounds.Known method comprises: (1) close electric halogenation, this halogen of reduction in the presence of the tritium source for example carry out hydrogenation with tritium gas in the presence of palladium catalyst, or (2) exchanges hydrogen with tritium in the presence of tritium gas and suitable organo-metallic (as palladium) catalyzer then.
Can be used for that exploitation combine with alpha 7 nicotinic acetylcholine receptors and by excitement, part excitement or the active new drug compound of antagonistic action adjusting this receptor with tritium-labeled The compounds of this invention.Above-mentioned tritium-labeled compound can be used for the displacement of analytical test above-claimed cpd with the bonding force of assessment with alpha 7 nicotinic acetylcholine receptors bonded part.
Another aspect of the present invention relates to compound and their purposes in treatment and the composition that contains them with formula I.
A concrete aspect of the present invention relates to the compound with formula I and is used for the treatment of purposes by the disease of the effect of nicotinic acetylcholine receptor mediation.The present invention relates in one aspect to the compound with formula I more specifically and is used for the treatment of purposes by the disease of the effect of alpha 7 nicotinic acetylcholine receptors mediation.
Another aspect of the present invention relates to that to treat or prevent the wherein activation of alpha 7 nicotinic receptor be the useful disease or the method for illness, and it comprises the The compounds of this invention to patient's drug treatment significant quantity of suffering from described disease or illness.
An embodiment of this aspect of the present invention is a kind of treatment or prevention method, and wherein said disease is anxiety disorder, schizophrenia, mania or manic depressive illness.
Another embodiment of this aspect of the present invention is the method for a kind of treatment or prevention sacred disease, mental disorder or amentia disease, and it comprises the The compounds of this invention of drug treatment significant quantity.
Another embodiment of this aspect of the present invention is a kind of treatment or prevention method, and wherein said disease is Alzheimer's, deficiency of learning ability, cognitive power disappearance, attention deficit, memory loss, scatterbrained hyperactivity disorder (Attention Deficit Hyperactivity Disorder).
Another embodiment of this aspect of the present invention is a kind of treatment or prevention method, and wherein said disease is Parkinson's disease, Huntington's disease, Tourette's syndrome, or the neurodegenerative disease of cholinergic synapse forfeiture is wherein arranged.
Another embodiment of this aspect of the present invention is the method for a kind of treatment or prevention jet lag (jetlag), nicotine addiction, one-tenth addiction, pain and ulcerative colitis, and it comprises the The compounds of this invention of drug treatment significant quantity.
Another embodiment of this aspect of the present invention is a kind of method of inducing smoking to give up, and it comprises the The compounds of this invention of effective dosage.
Another embodiment of this aspect of the present invention is a kind of pharmaceutical composition, and it comprises The compounds of this invention and at least a pharmaceutically acceptable diluent, lubricant or carrier.
Another aspect of the present invention relate in the preferred people of Mammals, be used for the treatment of or prevent this paper mentioned because the illness that caused of nicotinic acetylcholine receptor neurotransmission dysfunction or the pharmaceutical composition of disease, said composition comprises a certain amount of formula I compound, its enantiomer or its pharmaceutically useful salt and the pharmaceutically useful additive carrier that can effectively treat or prevent above-mentioned disease or illness.
Another embodiment of this aspect of the present invention is that pharmaceutical composition of the present invention is used for the treatment of, improves or prevent the wherein activation of alpha 7 nicotinic receptor is the useful human diseases or the purposes of illness.
Another embodiment of this aspect of the present invention is the purposes that pharmaceutical composition of the present invention is used for the treatment of or prevents sacred disease, mental disorder or amentia disease.
Another embodiment of this aspect of the present invention is that pharmaceutical composition of the present invention is used for the treatment of or prevents Alzheimer's, deficiency of learning ability, the cognitive power disappearance, attention deficit, memory loss, scatterbrained hyperactivity disorder, anxiety disorder, schizophrenia, mania or manic depressive illness, Parkinson's disease, Heng Tingdunshi disease, Tourette's syndrome, the neurodegenerative disease that the cholinergic synapse forfeiture is wherein arranged, jet lag, smoking is given up, nicotine addiction (comprising the habituation that product caused that contains Nicotine because of contact), become addiction, the purposes of pain and ulcerative colitis.
Another aspect of the present invention relates to The compounds of this invention, its enantiomer or its pharmaceutically useful salt and is used for the treatment of or prevents purposes in the medicine of mentioned disease of this paper or illness in preparation.
To be The compounds of this invention be used for the treatment of or prevent the wherein activation of alpha 7 nicotinic receptor in preparation another embodiment of this aspect of the present invention is purposes in the medicine of useful human diseases or illness.
To be The compounds of this invention be used for the treatment of or prevent purposes in the medicine of sacred disease, mental disorder or amentia disease in preparation another embodiment of this aspect of the present invention.
To be The compounds of this invention be used for the treatment of or prevent purposes in the medicine of Alzheimer's, deficiency of learning ability, cognitive power disappearance, attention deficit, memory loss, scatterbrained hyperactivity disorder in preparation another embodiment of this aspect of the present invention.
To be The compounds of this invention be used for the treatment of or prevention of anxiety disease, schizophrenia in preparation another embodiment of this aspect of the present invention, or the purposes in the medicine of mania or manic depressive illness.
To be The compounds of this invention be used for the treatment of or prevent Parkinson's disease, Heng Tingdunshi disease, Tourette's syndrome, wherein purposes in the medicine of neurodegenerative disease of cholinergic synapse forfeiture arranged in preparation another embodiment of this aspect of the present invention.
To be above-claimed cpd be used for the treatment of or prevent purposes in the medicine of jet lag, pain or ulcerative colitis in preparation another embodiment of this aspect of the present invention.
Another aspect of the present invention relates to The compounds of this invention and helps smoking to give up or treat nicotine addiction or become purposes in the medicine of addiction (comprise contain because of contact Nicotine product caused) in preparation.
For the mentioned such use of this paper, method, medicine and composition, the amount of compound used therefor and the dosage of administration should change with compound used therefor, administering mode and required treatment certainly.But, generally, when giving The compounds of this invention, can reach satisfied effect with the about 20mg/kg the weight of animals of the about 0.1mg-of per daily dose.Such dosage can be to be divided into the every day of 1-4 time dosed administration or with the slow release formulation administration.For the people, total per daily dose scope is from 5mg to 1,400mg, and more preferably 10mg to 100mg, the unit dosage that is suitable for oral administration comprises 2mg to 1, the described compound of 400mg and blended solid or liquid, medicinal carrier, lubricant and thinner with it.
Formula I compound, its enantiomer and pharmaceutically useful salt thereof can be used or use with its suitable pharmaceutical dosage forms through enteron aisle or parenteral administration with the form of itself.Another aspect of the present invention provides a kind of pharmaceutical composition, it comprise weight percent preferably less than 80%, be more preferably less than 50% The compounds of this invention, and blended inertia pharmaceutically acceptable diluent, lubricant or carrier with it.
The example of thinner, lubricant and carrier is as follows:
-be used for tablet and sugar-coat agent: lactose, starch, talcum, stearic acid;
-be used for capsule: tartrate or lactose;
-be used for injection liquid: water, alcohols, glycerine, vegetables oil;
-be used for suppository: natural or sclerosis oils or wax class.
The present invention also provides the method for preparing this pharmaceutical composition, and it comprises described component is mixed.
Compound of the present invention is the agonist of nicotinic acetylcholine receptor.Though be not limited to theory, the agonist that it is believed that alpha 7 nicotinic acetylcholine receptors (nAChR) hypotype should be useful to treatment or prevention sacred disease, mental disorder and amentia disease, and agonist that can exciting individually or simultaneously α 4nAChR hypotype more has superiority.Therefore, preferably α 7nAChR hypotype had optionally compound.It is as medicine that The compounds of this invention indicates, and particularly is used in the medicine of treatment or prevention sacred disease, mental disorder and amentia disease aspect.The example of mental disorder comprises schizophrenia, mania and manic depressive illness and anxiety disorder.The example of amentia disease comprises Alzheimer's, deficiency of learning ability, cognitive power disappearance, attention deficit, memory loss, scatterbrained hyperactivity disorder.The compounds of this invention also can be used as anodyne, is used for the treatment of pain, chronic pain and is used for the treatment of or prevents Parkinson's disease, Heng Tingdunshi disease, Tourette's syndrome, wherein the neurodegenerative disease of cholinergic synapse forfeiture arranged.
The compounds of this invention also can be used for treatment or prevention jet lag, is used to induce smoking to give up, become addiction, and is used for the treatment of or prevents nicotine addiction (comprising the habituation that product caused that contains Nicotine because of contact).
Believe that also The compounds of this invention is useful on treatment or prevention of ulcerative colitis.
The advantage that The compounds of this invention has than known therapeutical agent is that its toxicity is lower, more effective, action time is longer, have wideer field of activity, side effect more potent, that produce is littler, easier is absorbed or has other useful pharmacological properties.
Formula I compound exists tautomer or enantiomeric forms, and all these forms all is included in the scope of the present invention.Can adopt routine techniques,,, separate various optical isomers by separating the racemic mixture of described compound as fractionation crystallization or chirality HPLC.Perhaps, single enantiomer can get by making suitable optical activity starting raw material prepared in reaction under the reaction conditions that does not cause racemization.
General experimental technique and definition
Directly use without being further purified the commercial reagent.Use Hewlett Packard 5988A or MicroMass Quattro-1 mass spectrograph record mass spectrum, and the parent molecule ion is carried out record with m/z.Room temperature is meant 20-25 ℃.
SiO 2The chromatography operational circumstances is: use Isco CombiFlash Sq 16x instrument and the removable RediSep SiO of prepackage 2Stationary phase post (4,12,40,120g specification), with 5-125ml/ minute with the solvent pairs mixture gradient elution of selecting, UV detects (190-760nm scope) or collects 0.1mm chute path length by the time.
Use Personal Chemistry Smith synthesizer or Personal Chemistry Emrys optimizer (monotype, 2.45GHz, 300W maximum value) to realize microwave heating.
Supercritical fluid chromatography (SFC) is as the purifying mode of selected compounds and intermediate.
Anti-phase high pressure liquid chromatography (RP-HPLC) is as the purification process of selected compounds.
The general Agilent Zorbax 5 μ SB-C8 post 2.1mm * 5cm that use carry out LC/MS HPLC method.Solvent: A=contains the H of 0.05%TFA 2O, B=10%H 2O, 90% acetonitrile, 0.05%TFA.Gradient: (3 minutes 10-90%B, 90%B remained to 4 minutes, reduced to 10%B and remained on 10%B until 6 minutes in the time of 5 minutes).
Unless indication is arranged in addition, halogen comprises chlorine, bromine, fluorine and iodine; C 1-6Alkyl comprises propyl group, butyl, amyl group or the hexyl of methyl, ethyl and straight chain, ring-type or side chain; C 2-6Alkenyl comprises vinyl, 1-propenyl, 2-propenyl or 3-propenyl and straight chain, side chain or cyclic butenyl, pentenyl or hexenyl; C 2-6Alkynyl comprises ethynyl or proyl; As herein described separately or as other group partial C 1-4Alkyl can be a straight or branched, for example methyl, ethyl, n-propyl, normal-butyl, sec.-propyl, isobutyl-, the tertiary butyl, sec-butyl, and C 3-4Alkyl can also be a cyclic, for example cyclopropyl, cyclobutyl.Alkyl as herein described can randomly be substituted with 1,2 or 3 halogen atoms thereon.
Unless otherwise, aryl refers to benzyl ring, can choose wantonly by 1～3 substituting group that is selected from following radicals to replace: halogen, C 1-4Alkyl, C 2-4Alkenyl, C 2-4Alkynyl, NR 1R 2, CH 2NR 1R 2, OR 3, CH 2OR 3, CO 2R 4, CN, NO 2And CF 3
Unless otherwise, heteroaryl refers to comprise 5-or the 6-person's fragrance or the assorted aromatic nucleus of 0～3 nitrogen-atoms, 0 or 1 Sauerstoffatom and 0 or 1 sulphur atom, condition is that ring comprises at least one nitrogen, oxygen, or sulphur atom, and it is chosen wantonly by one or more substituting group that is selected from following radicals and replaces: halogen, C 1-4Alkyl, C 2-4Alkenyl, C 2-4Alkynyl, NR 1R 2, CH 2NR 1R 2, OR 3, CH 2OR 3, CO 2R 4, CN, NO 2And CF 3
Unless otherwise, halogen refers to fluorine, chlorine, bromine, or iodine.
Pharmaceutically useful derivative comprises solvate and salt.For example formula I compound can form acid salt as toxilic acid, hydrochloric acid, Hydrogen bromide, phosphoric acid, acetate, fumaric acid, Whitfield's ointment, citric acid, lactic acid, amygdalic acid, tartrate and methylsulfonic acid with sour as conventional pharmaceutically acceptable acid.
Pharmacology
With testing method as described below the pharmacological activity of The compounds of this invention is tested:
Test A-detects α 7The avidity of nAChR hypotype
125I-α-bungatotoxin (BTX) is to the combination test of rat hippocampus film.
With the cooled homogenate damping fluid (HB: concentration of component (mM): three (methylol) aminomethane 50 of rat hippocampus at 20 times of volumes; MgCl 21; NaCl 120; KCl 5:pH 7.4) homogenate in.With under homogenate 1000 * g centrifugal 5 minutes, keep supernatant liquor, extract throw out once more.Merge supernatant liquor, with 12000 * g centrifugal 20 minutes, washing was resuspended among the HB.With film (30-80 μ g) and 5nM [ 125I] CaCl of α-BTX, 1mg/mL BSA (bovine serum albumin), testing drug and 2mM 2Or the EGTA[ethylene glycol-two of 0.5mM (beta-amino ether)] under 21 ℃, hatched 2 hours, use the Brandel cell harvestor on Whatman glass fibre filter (thickness C), to filter and wash 4 times then.With the aqueous solution pre-treatment filter of 1% (BSA/0.01%PEI (polymine)) 3 hours, this was very crucial for low filter blank value (per minute grand total 0.07%).(-)-nicotine with 100 μ M is measured non-specific binding, and specificity is in conjunction with being generally 75%.
Test B-measures the avidity to α 4nAChR hypotype
[ 3H]-combination of (-)-nicotine.Application has been carried out improved method to Martino-Barrows and the described method of Kellar (Mol Pharm (1987) 31:169-174), by [ 125I] α-BTX is in conjunction with described in the test, with brain (cortex and the hippocampus) homogenate of rat, under 12,000 * g centrifugal 20 minutes, washed twice, and then be suspended among the HB of the hexafluorophosphoric acid diisopropyl ester that contains 100 μ M.After 4 ℃ are placed 20 minutes, with film (approximately 0.5mg) and 3nM [ 3H]-(-)-nicotine, testing drug, 1 μ M coromegine, and the CaCl of 2mM 2Or the EGTA one of 0.5mM arises from 4 ℃ and hatched 1 hour, uses the Brandel cell harvestor to go up and filter at Whatman glass fibre filter (thickness C) (with 0.5%PEI pre-treatment 1 hour) then.Carbachol with 100 μ M is measured non-specific binding, and specificity is in conjunction with being generally 84%.
The binding data analysis of test A and B
IC 50(DeLean A, Munson P J and Rodbard D (1977) Am.J.Physiol. 235:E97-E102) calculate with non-linear curve fitting program ALLFIT for value and pseudo-Hill coefficient (nH).With non-linear regression ENZFITTER (Leatherbarrow, R.J. (1987)) saturation curve is fitted to unit point model (one site model), obtain [ 125I]-α-BTX and [ 3H]-the KD value of (-)-nicotine part, be respectively 1.67 and 1.70nM.Cheng-Prusoff equation with routine comes calculating K iValue:
K i=[IC 50]/((2+ ([part]/[KD]) n) 1/n-1)
Wherein work as n H＜1.5 o'clock, n value=1; Work as n H〉=1.5 o'clock, n value=2.Sample test is adopted and is carried out in triplicate, and be generally ± 5%.Measure K with 6 or more a plurality of drug level iValue.
Binding affinity (the K of The compounds of this invention in test A or test B i) less than 10 μ M, show that their expections have therapeutic activity.
The mensuration of the outflow effect of test C-P-glycoprotein mediation
Adopt method as described below to go up the transhipment effect that detects P-glycoprotein mediation (Pgp) at the Madin-Darby Canidae nephrocyte (MDR1-MDCK) of people P-glycoprotein.
At 37 ℃ and 5%CO 2Under the condition, in containing the Du Erbeikeshi minimum essential medium (DMEM) of 10% foetal calf serum (FBS), cultivate MDR1-MDCK clone, go down to posterity weekly twice.
In order to implement this mensuration, with 300, the cell density of 000 cell/mL is inoculated in cell end face (the apical side of 12 hole Costar culture plates with every hole 0.5mL, A) or with 150, the cell density of 000 cell/mL is inoculated in cell in the 24 hole Falcon culture plates with every hole 0.4mL, and to striding substrate side, hole (transwell basolateral B) adds the substratum of 1.5mL (12 orifice plate) or 1mL (24 orifice plate) in the chamber.Upgrade substratum every day, inoculate the monolayer that forms after 3 days and be used for the transhipment test.Before transporting test, cultivated monolayer 2 hours.
Place chopsticks formulas (chopstick) electrode, its substratum with the monolayer both sides is contacted, and measure the resistance (the resistance across the monolayer) of striding monolayer.The normal value of striding monolayer resistance is 130-160Ohms/cm 2
Use 12 orifice plate manual controls to transport test, divide to run to end face (B to A) and end face in triplicate from the substrate side and run to substrate side (A to B) direction and test.Test compounds is dissolved among the DMSO and with HBSS is diluted to test concentrations, wherein final concentration＜1% of DMSO in test soln.Under 37 ℃, strode the hole 20 to 40 minutes, and prepare to replenish plate with the HBSS washing.
For the test of A to B, 1.5mL HBSS is added in the hand-hole then with in the 0.5mL test soln adding liner (insert).For the test of B to A, the 1.5mL test soln is added in the hand-hole then with in the 0.5mL HBSS adding liner.Liner is transferred to additional plate, and be in 37 ℃ of water-baths, to hatch this plate 60 minutes under the 70rpm in oscillation rate.During each off-test, take out described liner in the slave plate and sample is transferred in the HPLC bottle from supply chamber and reception chamber, use conventional LC/MS/MS method that it is analyzed.Use 0,0.005,0.05, and the calibration criterion of 0.5 μ M.
The result calculates:
Calculate apparent permeability according to following equation:
The ÷ of Papp=[(Vr * Cr) (A * t * Co)] * 1,000,000 (10 -6Cm/ second)
Rate of outflow=Papp (B-A)÷ Papp (A-B)
MB (% recovery)=[(Vr * Cr)+(Vd * Cd)] ÷ (Vd * Co) } * 100
Wherein: Vr=reception chamber volume cm 3Concentration in the time of Cr=60 minute in the reception chamber; Starting point concentration in the Co=supply chamber; Vd=supply chamber volume; Concentration in the time of Cd=60 minute in the supply chamber; A=strides the surface-area in hole and t=60 minute.
In this test, The compounds of this invention has the A-B/B-A ratio less than 2.5 usually.
Compound of the present invention
The compounds of this invention can prepare by following step: with the fragrance of suitable replacement or carboxylic acid (0.50mmol), the R-(+)-3-amino quinine ring dihydrochloride (100mg of assorted fragrance, 0.50mmol), I-hydroxybenzotriazole hydrate (68mg, 0.50mmol), O-(benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate (161mg, 0.50mmol) and diisopropyl ethyl amine (0.35mL, 2.0mmol) at exsiccant N, reacted at ambient temperature 23 hours in the dinethylformamide (2mL).Reaction mixture is poured in the 1N sodium hydroxide solution also with ethyl acetate extraction (3x).Ethyl acetate layer merges and washs with 1NNaOH (1x), water (4x), salt solution (1x), and at MgSO 4Last dry.After the filtration, vacuum is removed the compound that solvent obtains needs.
Following example is nonrestrictive and has embodied concrete aspect of the present invention.
N-(R)-1-azabicyclic [2.2.2] oct-3-yl-2-methyl-5-phenylbenzamaide;
N-(R)-1-azabicyclic [2.2.2] oct-3-yl-2-methyl-3-phenylbenzamaide;
(N-(R)-1-azabicyclic [2.2.2] oct-3-yl)-3-methyl-5-phenyl thiophene-2-carboxylic acid acid amides;
(N-(R)-1-azabicyclic [2.2.2] oct-3-yl)-3-methyl-5-(3-pyridyl) thiophene-2-carboxylic acid acid amides;
N-(R)-1-azabicyclic [2.2.2] oct-3-yl-2-carboxyl-5-phenylbenzamaide;
N-(R)-1-azabicyclic [2.2.2] oct-3-yl-2-carboxyl-3-phenylbenzamaide;
(N-(R)-1-azabicyclic [2.2.2] oct-3-yl)-3-carboxyl-5-phenyl thiophene-2-carboxylic acid acid amides;
(N-(R)-1-azabicyclic [2.2.2] oct-3-yl)-3-carboxyl-5-(3-pyridyl) thiophene-2-carboxylic acid acid amides;
N-(R)-1-azabicyclic [2.2.2] oct-3-yl-2-cyano group-5-phenylbenzamaide;
N-(R)-1-azabicyclic [2.2.2] oct-3-yl-2-cyano group-3-phenylbenzamaide;
(N-(R)-1-azabicyclic [2.2.2] oct-3-yl)-3-cyano group-5-phenyl thiophene-2-carboxylic acid acid amides;
(N-(R)-1-azabicyclic [2.2.2] oct-3-yl)-3-cyano group-5-(3-pyridyl) thiophene-2-carboxylic acid acid amides;
N-(R)-1-azabicyclic [2.2.2] oct-3-yl-2-amino-5-phenyl benzamide;
N-(R)-1-azabicyclic [2.2.2] oct-3-yl-2-amino-3-phenylbenzamaide;
(N-(R)-1-azabicyclic [2.2.2] oct-3-yl)-3-amino-5-phenyl thiophene-2-carboxylic acid acid amides, and
(N-(R)-1-azabicyclic [2.2.2] oct-3-yl)-3-amino-5-(3-pyridyl) thiophene-2-carboxylic acid acid amides.

Claims (20)

1. the formula I compound that has the outflow effect of low P-glycoprotein-mediation:
Wherein:
D represents oxygen or sulphur;
E represents singly-bound, oxygen, sulphur, or NR 1
Ar 1Be selected from 5-or the 6-person's fragrance or the assorted aromatic nucleus of ortho position replacement with 0,1 or 2 nitrogen-atoms, 0 or 1 Sauerstoffatom and 0 or 1 sulphur atom, or being selected from 8-, 9-or 10-person's condensed fragrance or the assorted aromatic nucleus system that ortho position with 0,1,2 or 3 nitrogen-atoms, 0 or 1 Sauerstoffatom and 0 or 1 sulphur atom replaces, described fragrance or assorted aromatic nucleus or member ring systems have and are selected from-C 1-C 6Alkyl ,-C 2-C 6Alkenyl ,-C 2-C 6Alkynyl, halogen ,-CN ,-NO 2,-CF 3,-S (O) nR 2,-NR 2R 3,-CH 2NR 2R 3,-OR 2,-CH 2OR 2Or-CO 2R 4Ortho position-substituting group;
Ar 2Be selected from 5-or 6-person's fragrance or assorted aromatic nucleus with 0,1 or 2 nitrogen-atoms, 0 or 1 Sauerstoffatom and 0 or 1 sulphur atom;
Ar wherein 2Be unsubstituted or have 1,2 or 3 and be independently selected from-R 2,-C 1-C 6Alkyl ,-C 2-C 6Alkenyl ,-C 2-C 6Alkynyl, halogen ,-CN ,-NO 2,-CF 3,-S (O) nR 2,-NR 2R 3,-CH 2NR 2R 3,-OR 2,-CH 2OR 2Or-CO 2R 4Substituting group;
R 2And R 3The each appearance, be independently selected from hydrogen ,-C 1-C 4Alkyl, aryl, heteroaryl ,-C (O) R 4,-C (O) NHR 4,-CO 2R 4Or-SO 2R 4, or
R 2And R 3Be combined into-(CH 2) jG (CH 2) k-, wherein G is oxygen, sulphur, NR 4, or chemical bond;
J is 2,3 or 4;
K is 0,1 or 2;
N is 0,1 or 2, and
R 4The each appearance, be independently selected from hydrogen ,-C 1-C 4Alkyl, aryl, or heteroaryl, and
Hydrolyzable precursor and pharmaceutically useful salt in its steric isomer, enantiomer, the body.
2. according to the compound of claim 1, it is the R-isomer of the formula I compound of Formula Il,
Figure A2004800412790003C1
Wherein D, Ar 1, E and Ar 2Define suc as formula the I compound.
3. according to the compound of claim 1, wherein:
D represents oxygen or sulphur;
E represents singly-bound, oxygen, sulphur, or NR 1
Ar 1Be selected from 5-or the 6-person's fragrance or the assorted aromatic nucleus of ortho position replacement with 0,1 or 2 nitrogen-atoms, 0 or 1 Sauerstoffatom and 0 or 1 sulphur atom, or being selected from 8-, 9-or 10-person's condensed fragrance or the assorted aromatic nucleus system that ortho position with 0,1,2 or 3 nitrogen-atoms, 0 or 1 Sauerstoffatom and 0 or 1 sulphur atom replaces, described fragrance or assorted aromatic nucleus or member ring systems have and are selected from-C 1-C 6Alkyl, halogen ,-CN ,-NO 2,-CF 3,-NR 2R 3,-OR 2, or-CO 2R 4Ortho position-substituting group;
Ar 2Be selected from 5-or 6-person's fragrance or assorted aromatic nucleus with 0,1 or 2 nitrogen-atoms, 0 or 1 Sauerstoffatom and 0 or 1 sulphur atom;
Ar wherein 2Be unsubstituted or have 1,2 or 3 and be independently selected from-R 2,-C 1-C 6Alkyl ,-C 2-C 6Alkenyl ,-C 2-C 6Alkynyl, halogen ,-CN ,-NO 2,-CF 3,-S (O) nR 2,-NR 2R 3,-CH 2NR 2R 3,-OR 2,-CH 2OR 2Or-CO 2R 4Substituting group;
R 2And R 3The each appearance, be independently selected from hydrogen ,-C 1-C 4Alkyl, aryl, heteroaryl ,-C (O) R 4,-C (O) NHR 4,-CO 2R 4Or-SO 2R 4, or
R 2And R 3Be combined into-(CH 2) jG (CH 2) k-, wherein G is oxygen, sulphur, NR 4, or chemical bond;
J is 2,3 or 4;
K is 0,1 or 2;
N is 0,1 or 2, and
R 4The each appearance, be independently selected from hydrogen ,-C 1-C 4Alkyl, aryl, or heteroaryl, and
Hydrolyzable precursor and pharmaceutically useful salt in its steric isomer, enantiomer, the body.
4. according to the compound of claim 1, wherein:
D represents oxygen;
E represents singly-bound;
Ar 1Be selected from 5-or 6-person's fragrance or assorted aromatic nucleus that ortho position with 0,1 or 2 nitrogen-atoms, 0 or 1 Sauerstoffatom and 0 or 1 sulphur atom replaces, described fragrance or assorted aromatic nucleus have and are selected from-C 1-C 6Alkyl, halogen ,-CN ,-NO 2,-CF 3,-NR 2R 3,-OR 2Or-CO 2R 4Ortho position-substituting group;
Ar 2Be selected from 5-or 6-person's fragrance or assorted aromatic nucleus with 0,1 or 2 nitrogen-atoms, 0 or 1 Sauerstoffatom and 0 or 1 sulphur atom, and
Hydrolyzable precursor and pharmaceutically useful salt in its steric isomer, enantiomer, the body.
5. according to the compound of claim 1, wherein:
D represents oxygen;
E represents singly-bound;
Ar 1Be selected from 5-or 6-person's fragrance or assorted aromatic nucleus that ortho position with 0,1 or 2 nitrogen-atoms, 0 or 1 Sauerstoffatom and 0 or 1 sulphur atom replaces, described fragrance or assorted aromatic nucleus have be selected from-CN ,-NO 2,-CF 3, or-OR 2Ortho position-substituting group;
Ar 2Be selected from phenyl or pyridyl, and
Hydrolyzable precursor and pharmaceutically useful salt in its steric isomer, enantiomer, the body.
6. according to the compound of claim 1, wherein:
D is O; Or its enantiomer, with and pharmaceutically useful salt.
7. according to the compound of claim 1, wherein:
Ar 1Be selected from phenyl or thienyl and Ar 2Be selected from and have optional as defined above substituent phenyl, pyridyl, furyl or thienyl.
8. according to the compound of claim 1, be selected from:
N-(R)-1-azabicyclic [2.2.2] oct-3-yl-2-methyl-5-phenylbenzamaide;
N-(R)-1-azabicyclic [2.2.2] oct-3-yl-2-methyl-3-phenylbenzamaide;
(N-(R)-1-azabicyclic [2.2.2] oct-3-yl)-3-methyl-5-phenyl thiophene-2-carboxylic acid acid amides;
(N-(R)-1-azabicyclic [2.2.2] oct-3-yl)-3-methyl-5-(3-pyridyl) thiophene-2-carboxylic acid acid amides;
N-(R)-1-azabicyclic [2.2.2] oct-3-yl-2-carboxyl-5-phenylbenzamaide;
N-(R)-1-azabicyclic [2.2.2] oct-3-yl-2-carboxyl-3-phenylbenzamaide;
(N-(R)-1-azabicyclic [2.2.2] oct-3-yl)-3-carboxyl-5-phenyl thiophene-2-carboxylic acid acid amides;
(N-(R)-1-azabicyclic [2.2.2] oct-3-yl)-3-carboxyl-5-(3-pyridyl) thiophene-2-carboxylic acid acid amides;
N-(R)-1-azabicyclic [2.2.2] oct-3-yl-2-cyano group-5-phenylbenzamaide;
N-(R)-1-azabicyclic [2.2.2] oct-3-yl-2-cyano group-3-phenylbenzamaide;
(N-(R)-1-azabicyclic [2.2.2] oct-3-yl)-3-cyano group-5-phenyl thiophene-2-carboxylic acid acid amides;
(N-(R)-1-azabicyclic [2.2.2] oct-3-yl)-3-cyano group-5-(3-pyridyl) thiophene-2-carboxylic acid acid amides;
N-(R)-1-azabicyclic [2.2.2] oct-3-yl-2-amino-5-phenyl benzamide;
N-(R)-1-azabicyclic [2.2.2] oct-3-yl-2-amino-3-phenylbenzamaide;
(N-(R)-1-azabicyclic [2.2.2] oct-3-yl)-3-amino-5-phenyl thiophene-2-carboxylic acid acid amides, or
(N-(R)-1-azabicyclic [2.2.2] oct-3-yl)-3-amino-5-(3-pyridyl) thiophene-2-carboxylic acid acid amides,
Or its pharmaceutically useful salt.
9. a treatment or to prevent the wherein activation of alpha 7 nicotinic acceptor be the useful disease or the method for illness, this method comprises the compound according to claim 1 to patient's drug treatment significant quantity of suffering from described disease or illness.
10. according to the method for claim 9, wherein said disease or illness are anxiety disorder, schizophrenia, mania or manic depressive illness.
11. the method for the treatment of or preventing sacred disease, mental disorder or amentia disease, it comprises the compound according to claim 1 of drug treatment significant quantity.
12. according to the method for claim 11, wherein said disease is Alzheimer's, deficiency of learning ability, cognitive power disappearance, attention deficit, the loss of memory, scatterbrained hyperactivity disorder, Parkinson's disease, huntington disease, Tourette's syndrome, wherein neurodegenerative disease, jet lag, nicotine addiction, one-tenth addiction, pain or the ulcerative colitis of cholinergic synapse disappearance.
13. a method of inducing smoking to give up, it comprises the compound according to claim 1 of effective dosage.
14. a pharmaceutical composition, it comprises according to the compound of claim 1 and acceptable diluents, lubricant or carrier.
15. one kind is treated or prevents the wherein activation of alpha 7 nicotinic acceptor is the useful disease or the method for illness, this method comprises the pharmaceutical composition according to claim 14 to patient's drug treatment significant quantity of suffering from described disease or illness.
16. according to the method for claim 15, wherein said disease or illness are anxiety disorder, schizophrenia, mania or manic depressive illness.
17. the method for the treatment of or preventing sacred disease, mental disorder or amentia disease, it comprises the pharmaceutical composition of the claim 14 of drug treatment significant quantity.
18. according to the method for claim 15, wherein said disease is Alzheimer's, deficiency of learning ability, cognitive power disappearance, attention deficit, the loss of memory, scatterbrained hyperactivity disorder, Parkinson's disease, huntington disease, Tourette's syndrome, wherein neurodegenerative disease, jet lag, nicotine addiction, one-tenth addiction, pain and the ulcerative colitis of cholinergic synapse disappearance.
19. a method of inducing smoking to give up, it comprises the pharmaceutical composition according to claim 14 of effective dosage.
20. compound according to claim 1, its enantiomer or its pharmaceutically useful salt are used for the treatment of or prevent the wherein activation of alpha 7 nicotinic acceptor in preparation is purposes in the medicine of useful human diseases or illness, described disease or illness are selected from sacred disease, mental disorder, the amentia disease, Alzheimer's, deficiency of learning ability, the cognitive power disappearance, attention deficit, the loss of memory, scatterbrained hyperactivity disorder, anxiety disorder, schizophrenia, mania or manic depressive illness, Parkinson's disease, huntington disease, Tourette's syndrome, or the neurodegenerative disease of cholinergic synapse disappearance wherein.
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